Mathematical Modeling of Remdesivir to Treat COVID-19: Can Dosing Be Optimized?
Abstract
:1. Introduction
2. Materials and Methods
2.1. Pharmacokinetic Model
2.2. Pharmacodynamics Model
2.3. Concentrations Selecting for Resistance
2.4. Model Validation: Recapitulation of In Vitro Experiments
3. Results
3.1. Standard Dosing Does Not Achieve Effective Concentrations
3.2. Model-Predicted Optimal Dosing Rate
3.3. Improved Dosing with RDV Doses That Were Tested in Phase I Trials
3.4. Alternative: Longer Infusion
3.5. Avoiding a Potential DR Mutant
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
EC | Half-maximal effective concentration |
EMA | European Medecines Agency |
FDA | US Food and Drug Administration |
IC | Half-maximal inhibitory concentration |
LRT | Lower respiratory tract |
MERS-CoV | Middle East respiratory syndrome coronavirus |
PBMCs | Peripheral blood mononuclear cells |
PK | Pharmacokinetic |
PD | Pharmacodynamic |
TE | Target engagement |
RdRp | RNA-dependent RNA polymerase |
RDV | Remdesivir |
RDV-TP | Remdesivir’s active triphosphate metabolite, GS-443902 |
URT | Upper respiratory tract |
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Parameter | Description | Units | Value |
---|---|---|---|
Remdesivir | |||
Dose | Total mass of RDV infused | mg | varies |
Duration of infusion | h | varies | |
Apparent volume | L | 6.09 | |
Elimination rate | per hour | 4.16 | |
k | Periphery-to-plasma RDV concentration | per hour | 0.13 |
transition rate | |||
Plasma-to-periphery RDV concentration | per hour | 4.42 | |
transition rate | |||
d | Nonlinear plasma RDV to RDV-TP | mg/L/h | 31.57 |
(intracellular GS-443902) transport and | |||
activation rate | |||
Conversion of concentrations from mg/L | mol/mg | 1 | |
to M | |||
D | RDV concentration yielding 50% of the | mg/L | 3516.27 |
maximal transport/activation rate | |||
Remdesivir concentration in the periphery | |||
Elimination rate | per hour | 1.55 | |
RDV-TP (Intracellular GS-433902) | |||
Linear elimination rate of RDV-TP | per hour | 1.55 | |
Nonlinear elimination rate of RDV-TP | M/h | ||
M | RDV-TP concentration at which the | M | 17.19 |
nonlinear elimination rate is 50% its | |||
maximum |
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Conway, J.M.; Abel zur Wiesch, P. Mathematical Modeling of Remdesivir to Treat COVID-19: Can Dosing Be Optimized? Pharmaceutics 2021, 13, 1181. https://doi.org/10.3390/pharmaceutics13081181
Conway JM, Abel zur Wiesch P. Mathematical Modeling of Remdesivir to Treat COVID-19: Can Dosing Be Optimized? Pharmaceutics. 2021; 13(8):1181. https://doi.org/10.3390/pharmaceutics13081181
Chicago/Turabian StyleConway, Jessica M., and Pia Abel zur Wiesch. 2021. "Mathematical Modeling of Remdesivir to Treat COVID-19: Can Dosing Be Optimized?" Pharmaceutics 13, no. 8: 1181. https://doi.org/10.3390/pharmaceutics13081181
APA StyleConway, J. M., & Abel zur Wiesch, P. (2021). Mathematical Modeling of Remdesivir to Treat COVID-19: Can Dosing Be Optimized? Pharmaceutics, 13(8), 1181. https://doi.org/10.3390/pharmaceutics13081181